L0301P14 - Role of the Liver in Metabolism and Detoxification Part 1
__TOC__ Functions of the Liver *distribution and processing plant - sorting and interconversion of digested foods *carbohydrate, lipid and amino acid metabolism (and regulation of C/L) *synthesis of urea *synthesis/breakdown of plasma proteins *vitamin and mineral metabolism *disposal of drugs, toxins and hormones Carbohydrate Metabolism in the Liver *synthesis and breakdown of glycogen *synthesis of glucose *cori cycle (lactic acid cycle) *glucose alanine cycle *glycolysis (glucose —> pyruvate) Sources of Blood Glucose *Dietary **peaks after meals *Glycogenolysis **break down of glycogen **decreases after meals **peaks in between meals *Gluconeogenesis **synthesis of glucose **peaks during fasting stage (e.g. sleep) **occurs slightly between meals Glycogen *polysaccharide of glucose *100s of glucose units - shrinks and grows depending on nutritional status *highly branched chain *two types of glycosidic bonds **α1—> 4 within the chain **α1—> 6 at branch points *most stored in muscle (only provides energy to the muscles themselves) *some in liver (provides for the rest of the body thus most important) and blood/ECF Branching *makes glycogen more soluble *increases the number of non-reducing ends = more sites accessible to glycogen synthase and glycogen phosphorylase *branches are created by an enzyme that cleaves the normal chain and attaches it as a branch Hormones Involved Insulin *stimulates glycogenesis *increase uptake of glucose from blood *inhibits glycogen phosphorylase, favours glycogen synthase *produced in β pancreatic cells Glucagon *stimulates glycogenolysis *increases glycogen breakdown *favours glycogen phosphorylase, inhibits glycogen synthase *produced in α pancreatic cells Glycogenesis *synthesis of glycogen - endergonic *activated after a carbohydrate rich meal *enzymes involved: **glycogenin - primer (starting pt) enzyme **glycogen synthase - regulated, requires UDP glucose **glucokinase - a hexokinase found in the liver - converts glucose to glucose-6-phosphate *G6P - glucose 6 phosphate *G1P - glucose 1 phosphate *UDP - uridine diphosphate (never altered) Process #glucose enter hepatocytes (liver cells) freely via Glut2 transporters #converted (phosphorylated) to G6P by glucokinase (type of hexokinase found specifically in the liver) #converted to G1P by phosphoglucomutase #converted to UDP-glucose by UDP-glucose phosphorylase #extend growing chain by adding a UDP-glucose (UDP is cleaved off) by glycogen synthase Glycogenolysis *mobilises stored glycogen for conversion to glucose *ATP producing reaction - exergonic *activated between meals Process #glycogen phosphorylase #*moves along the non-reducing end of the glycogen chain #*cleaves glucose off at α1—> 4 bonds forming G1P (rate limiting - cannot cleave at branch sites - approx. 4 glucoses off) #This is a rate limiting step  transferase (the deb ranching enzyme) #*cleaves branches at α1—> 6 bonds approx. 1 glucose off the branch point #*attaches the branch to the end of the unbranched chain so glycogen phosphorylase can continue #*glucosidase cleaves final glucose at the branch point #G1P converted to G6P by phosphoglucomutase so the mobilised glucose can be released Regulation and Control Hormonal Control *why: liver will use less glucose and more lipid for energy when glycogenolysis is activated Phosphorylation Control *Glycogen breakdown favoured: **synthase is phosphorylated which makes it less active while phosphorylase is phosphorylated to make it more active *Glycogen Synthesis Favoured: **no phosphorylation *Enzymes: **Kinase = add phosphate **Phosphatase = removes phosphate Defects *can occur in enzymes *therefore leads to a deficiency of the specific enzymes **leading to serious issues, e.g.: ***altered glycogen structure ***no glycogenolysis **blood glucose level problems Gluconeogenesis (GNG) *endergonic synthesis of glucose *used when glycogen stores have been exhausted (during fasting and starvation) *slower response than glycogen breakdown *primary source of glucose about 8 hours into the post absorptive state *initial carbon chain can be sourced from: **lactate **glucogenic amino acids **triglycerides - glycerol *reverse of glycolysis but there are three irreversible steps so bypass pathways with different enzymes are used instead *under control of insulin and glucagon ---- GNG from Glucogenic Amino Acids *amino acids broken down to either pyruvate or the CAC intermediates *some amino acids are ketogenic or gluconeogenic, or rarely, both *used as precursors for gluconeogenesis Process #transanimase catabolises the amino acid into an amino group and the carbon skeleton #oxidised into glutamate or alanine #*Glutamate - glutamine - moves to kidney and covered to glucose #*Alanine - released into bloodstream from muscle, taken up by the liver and converted to glucose ---- GNG from Lactate *end product of anaerobic glycolysis *allows hepatic recycling of lactate back to glucose *no net gain of glucose (as the lactate was produced from glucose in the first place) Process #muscle lactate released into bloodstream #taken up by liver cells converted to pyruvate by lactate dehydrogenase #enters the Cori Cycle and converted back to glucose using ATP